Heterocycles from ketones

The problem of the synthesis of highly substituted olefins from ketones according to this principle was solved by D.H.R. Barton. The ketones are first connected to azines by hydrazine and secondly treated with hydrogen sulfide to yield 1,3,4-thiadiazolidines. In this heterocycle the substituents of the prospective olefin are too far from each other to produce problems. Mild oxidation of the hydrazine nitrogens produces d -l,3,4-thiadiazolines. The decisive step of carbon-carbon bond formation is achieved in a thermal reaction a nitrogen molecule is cleaved off and the biradical formed recombines immediately since its two reactive centers are hold together by the sulfur atom. The thiirane (episulfide) can be finally desulfurized by phosphines or phosphites, and the desired olefin is formed. With very large substituents the 1,3,4-thiadiazolidines do not form with hydrazine. In such cases, however, direct thiadiazoline formation from thiones and diazo compounds is often possible, or a thermal reaction between alkylideneazinophosphoranes and thiones may be successful (D.H.R. Barton, 1972, 1974, 1975). 

Further exploitation of the molecular shape feature has led more recently to the design of another series of clathrate hosts by substituting on the allene rigid backbone bulky groups 22>, Representative compounds of this new host family are 20 and 21. The allene 20 (R = t-butyl) shows an interesting clathration behaviour upon crystallization from various environments, including alicyclic and aromatic compounds, heterocycles, cyclic ketones and eyclohexaneamine 26>. 

A palladium-catalyzed one-step synthesis of dihydrobenzo[fc]furan-based fused aromatic heterocycles from bifunctional bromoenoates or bromoalkyl indoles and iodoarenes was reported, and an example is provided in the scheme below <060L3601>. 2-Alkyl- or 2-aryl-substituted benzo[ >]furans were synthesized by a copper-TMEDA catalyzed intramolecular annulation from the corresponding ketones <06OL1467>. 

Felder ER, Marzinzik AL (1998) Key intermediates in combinatorial chemistry access to various heterocycles from a, 3-unsaturated ketones on solid phase. J Org Chem 63 723-727... 

The Pfitzinger reaction provides a simple and convenient method for the synthesis of condensed polycyclic compounds containing a heterocycle from readily obtainable starting materials. Cyclic ketones and, more rarely, diketones are often used as starting compounds. 

Fig. 13.35. Enders RAMP method for the generation of enantiomerically pure a-alky-lated carbonyl compounds RAMP, (/ )-aminoprolinol methyl ether or R-l-amino-2-(methoxymethyl)pyrrolidine. While hydrazones derived from ketones, such as compound E, are methylated at the doubly bound nitrogen, the methyla-tion of the corresponding aldehyde-derived hydrazones preferentially occurs at the nitrogen atom of the heterocycle.

Various substrates have been successfully used in the present LASC-catalysed aldol reaction. Aromatic as well as aliphatic, a, 3-unsaturated and heterocyclic aldehydes worked well. As for silicon enolates, silyl enol ethers derived from ketones as well as ketene silyl acetals derived from thioesters and esters reacted well to give the corresponding adducts in high yields. It is noted that highly water-sensitive ketene silyl acetals reacted smoothly in water under these conditions. 

Among heterocyclic derivatives obtained from ketonic Mannich bases, nitrogen-containing rings are by far the most prevalent, and the products involved arc quite numerous and varied. As a consequence, only selected synthetic methods are mentioned here. 

In the synthesis of various heterocycles from a-amino ketones, pyrazine formation can be a complicating side reaction due to the tendency of the a-amino ketone to dimerize. One way of avoiding this problem would be to generate the a-amino ketone in a protected form, specifically, as an a-amino acetal. Such derivatives allow the manipulation of the amino moiety as desired. Accordingly, the azirine intermediates derived from oxime tosylates by the Neber rearrangement are subsequently treated with acidic ethanol to furnish the corresponding a-amino acetals (equation 65). ° ... 

Intramolecular heterocyclization in polyacrylonitrile 86UK62. a-Isocyano acetates, synthesis of N-heterocycles from 85YGK764. Isonitrosotosyl malonates in synthesis of N-heterocycles 80H(14)1581. Lactams, regioselective formation from bridged bicyclic ketones 81T1283. Malononitrile derivatives, synthesis of N-heterocycles condensed from ... 

Many research groups have started with PPACK and produced inhibitors of a less peptidic nature (to improve in vivo stabihty), and/or with conformational restriction (to tackle the entropy loss problem), and/or with a variety of serine trap functionalities, for example, aldehydes, boronic acids, a-keto amides and acids, a-keto heterocycles, polyfluorinated ketones, and phosphonates. Structures of many of these are known in complex with thrombin but will not be reviewed here (see e.g., pubhca-tions of C.A. Kettner and coworkers). As well as lack of specificity, these potential drugs suffer from slow on-rates and have not progressed to the market. 

In addition to several general reviews on enamine chemistry, all of which include heterocyclic syntheses, there is an extensive survey by Hickmott which is entirely concerned with the formation of heterocycles. More specialized reviews deal with heterocyclic enamines, enaminones, the photochemistry of enamides , heterocyclic jS-enamino esters , enamino thiones , the synthesis of indole alkaloids via enamines , formation of pyrimidines, pyridopyrimidines, pyridines and pyrrolizines from enamines , synthesis of lactams , formation of heterocycles from cyclic enamino ketones and 2-acetylcyclohexen-l-ones, the synthesis of 3-cyano-2(l -pyrimidine-thiones and -selenones from jS-enamino ketones and the chemistry of cyclic en-aminonitriles. ... 

Other synthetic applications derive from various cyclizations that occur during reduction of the substrates that contain a reactive function at a specific position. These cyclizations proceed through the intermediate imine or amine to the cyclic amine. Various functional units such as olefins, heterocyclic rings, ketones, acids, amides, amines, nitrile, and nitro have been involved. Palladium, Rh, and finely divided Ni (Raney Ni) under more vigorous conditions are commonly used. Reductive cyclization of ketonitrile 1 over Raney Ni gives myosmine 2 along with some nomicotine 3 as overreduced product ... 

The ease of ring formation helped us to make five-membered cyclic acetals from ketones and a seven-membered heterocyclic compound (see Chapter 6). In this chapter we have seen how three-membered epoxides are formed. Ring formation is generally preferred to bimolecular reactions forming open chain compounds providing that the ring is three-, five-, six-, or seven-membered. Four-membered ring are a special case discussed in Chapter 29 where all these points are developed more fully. 

Compared with aldehydes, most ketones are reduced relatively slowly by complex boron hydrides, and a method of distinguishing aldehydes from ketones has been developed on the basis of these differing reaction velocities.382 On the same principle, selective reduction of the aldehyde group can be effected without reduction of a keto group.381 There are, however, numerous examples of the reduction of aliphatic, alicyclic, aromatic, and heterocyclic ketones by complex boron hydrides. 

Heterocycles. Synthesis of substituted pyridines and quinolines from ketones, via dienamines and A -arylimines, respectively, is by extraction of the [CH] unit from reagent 1. 

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